title: Reversible inhibition can profoundly mislead studies on progressive inhibition of enzymes: the interaction of paraoxon with soluble neuropathy target esterase.
abstract: Neuropathy target esterase (NTE) is suggested to be the molecular target for the initiation of the organophosphorus induced delayed polyneuropathy (OPIDP). O,O'-diethyl p-nitrophenyl phosphate (paraoxon) was the non-neurotoxic OP of choice for the standard assay of NTE to block the non-relevant esterases (phenylvalerate hydrolases) because it was supposed not to inhibit the enzymic activity of the target protein while N,N'-diisopropyl phosphorodiamidofluoridate (mipafox) is the neuropathic OP used to inhibit (and so to detect) NTE activity. A soluble form of NTE (S-NTE) had previously been described in peripheral nerve which showed a different inhibitor response from that of the particulate NTE (P-NTE). The use of a sequential type of inhibition protocol revealed the presence of an activity component within S-NTE which was extremely sensitive to different esterase inhibitors. Such a soluble activity component remained hidden under the usual concurrent inhibition procedure with paraoxon and was about one order of magnitude more sensitive than P-NTE to the inhibitors studied in the present article. Our results suggest that paraoxon could produce a strong reversible effect on S-NTE when the concurrent procedure is used so that it interferes with its inhibition by both neuropathy inducers and promoters. As a result S-NTE seems to be much more sensitive, than previously believed, to several esterase inhibitors involved in either the genesis of delayed polyneuropathy and/or axonopathy promotion.
authors.affiliation: Universidad Miguel Hernández, Laboratorio de Neurotoxicología, Alicante, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Barril
authors.forename: E
authors.initials: E
authors.lastname: Vilanova
mesh_terms: D000818:Animals; D015415:Biomarkers; D002265:Carboxylic Ester Hydrolases / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000378:metabolism; D002645:Chickens; D004791:Enzyme Inhibitors / Q000378:metabolism*; D010261:Paraoxon / Q000633:toxicity*; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced; D012584:Sciatic Nerve / Q000187:drug effects / Q000201:enzymology*; D012995:Solubility; D013379:Substrate Specificity
chemical_list: D015415:Biomarkers; D004791:Enzyme Inhibitors; D002265:Carboxylic Ester Hydrolases; C021859:neurotoxic esterase; D010261:Paraoxon